Magnetic resonance imaging correlates of neuronal degeneration of brain stem nuclei in Parkinson’s disease

Schwarz, Stefan Theodor (2016) Magnetic resonance imaging correlates of neuronal degeneration of brain stem nuclei in Parkinson’s disease. PhD thesis, University of Nottingham.

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by a loss of pigmented dopaminergic neurons in the substantia nigra (SN) pars compacta and loss of pigmented noradrenergic neurons in the locus coeruleus (LC). Diagnosing PD can be challenging, especially in the early stages particularly when the typical movement disorder symptoms such as tremor, rigidity, bradykinesia and postural instability are not easily identifiable. Despite well-established PD clinical diagnostic criteria there is a misdiagnosis rate of up to 15% by neurology specialists and 25 % by general practitioners. The only approved diagnostic test to confirm suspected PD in a tremulous patient is dopamine transporter single photon emission tomography (DaTScanTM). This test is costly (£800 – 1500 in the UK) and has limited geographical availability in the UK. It involves exposure to ionising radiation and can only be used to assess the integrity of the dopaminergic system. Therefore there is a strong need for better and more accessible diagnostic tests for PD. The aim of this thesis is to investigate the sensitivity and specificity of three different MRI techniques as potential biomarkers of PD. MRI at 3T field strength was used in this thesis to demonstrate PD pathology in the pigmented brain stem nuclei of SN, LC and the ventral tegmental area (VTA). The objective was to develop new, easily accessible and affordable disease markers to help clinicians to establish the correct diagnosis early.

A promising technique, which is based on the assessment of free motion of water-associated protons in tissue, is termed diffusion tensor imaging (DTI). The amount of free motion in all directions of protons in tissues like the brain can be described using mean diffusivity (MD) as a measure. Diffusion in tissues like the brain is often limited (“restricted”) in certain directions. For example diffusion across the myelin sheaths of nerve-fibres in the brain white matter is constrained, whereas along the direction of the nerve fibre protons can diffuse freely. This is termed anisotropic diffusion and can be described using fractional anisotropy as a measure (FA). Microstructural PD pathological processes may alter these measures of diffusivity especially in the area of the early affected brain region of the SN. In a prospective case control study of 30 patients and 22 controls diffusion tensor imaging alterations of the SN were investigated by measuring regional alterations of fractional FA and MD. In addition, a systematic literature review and meta-analysis was performed to determine the evidence for nigral DTI alterations throughout the literature. The case control study did demonstrate a small but significant increase of nigral MD; however the meta-analysis did not confirm this result when synthesizing effect sizes of nine identified relevant studies. No significant PD induced FA alterations were found in the prospective case control study. The meta-analysis of nigral FA changes did likewise not show significant FA decrease after correcting for studies with unusual high FA measures in the control arm population. In summary the meta-analysis and the results of the case control study did not confirm that standard DTI measurements of the SN are reliable biomarkers of PD pathology.

In a further case-control study MRI sequences tracking the neuromelanin content of the pigmented brain stem nuclei like the SN, LC and the ventral tegmental area were investigated. PD induced decline of neurons in these nuclei causes depigmentation due to loss of neuromelanin content. In this study (including data from 24 PD patients and 20 controls) I found that only little neuromelanin related signal could be observed in the ventral tegmental area and there was no significant difference between patients with PD and controls. However, there were significant signal alterations of the SN and LC signal when comparing between the two groups. The neuromelanin related signal loss was most pronounced in the posterior SN even in the earlier stages of the disease. The signal loss in the anterior SN was less severe and correlated with the unified PD rating scale (UPDRS) and Hoehn and Yahr score as a measure of disease severity. The neuromelanin related signal reduction was significant but less extensive in the region of the LC when compared to the SN. The signal alterations in the LC did not correlate with the UPDRS or the Hoehn and Yahr score.

In the third part of the experimental section of this thesis, a further prospective case-control study of 19 participants (10 patients with PD) and retrospective study of 105 clinical cases (9 patients with PD) was performed. A high resolution SWI/T2* ‘iron sensitive’ sequence was used to assess MRI changes of the nigrosome-1. Nigrosomes are little islands of dopaminergic cells with physiologically low iron content. The healthy hyperintense signal of the linear shaped nigrosome-1 surrounded by the iron containing low signal SN regions has great resemblance to the appearance of a swallow tail. The PD induced pathological signal reduction within nigrosome-1 resulted in a loss of the typical ‘swallow tail appearance’. Visual qualitative assessment of the MRI scans for absence and presence of nigrosome-1 revealed high sensitivity and specificity (80-100% and 86-89% respectively) to allow differentiation of PD from healthy controls and non-PD patients.

In summary I found that standard nigral DTI is not reliable as a PD biomarker. Nigrosome and neuromelanin weighted MRI offers great potential for development into a clinically useful biomarker. Comparing the two techniques, nigrosome imaging has some advantages over neuromelanin weighted imaging: the high resolution SWI/T2* sequence is shorter (2-5 min versus 7-14 min neuromelanin MRI. However, further optimization of neuromelanin MRI sequences may be able to shorten the acquisition time. A further advantage of nigrosome MRI is that the images can be visually assessed for pathological alterations without the need for complicated analysis or data processing. A disadvantage of high resolution SWI/T2* is that it is more prone to artefacts. An advantage of neuromelanin weighted MRI is that changes especially in the anterior substantia nigra correlate to measures of disease severity like the UPDRS, although there is some early evidence from pilot studies that nigrosome imaging (at field strengths of 7T) may also be useful to assess disease severity related changes. Which of the two techniques is better suited to monitor longitudinal progressive PD related changes has to be assessed in future studies.

In conclusion standard nigral DTI measures have no proven value as a reliable diagnostic marker of PD. High resolution T2*/SWI MRI and neuromelanin weighted MRI of PD induced alteration of pigmented brain stem neurons distinguish PD from non-PD and control subjects with high sensitivity and specificity. Neuromelanin related alterations especially of the anterior SN correlate to disease severity measures like the UPDRS and therefore have potential as disease progression marker. The easy applicability of the ‘swallow tail sign’ to indicate a healthy nigrosome-1 in the SN may well prove a useful marker to help the clinical diagnosis of PD. If future studies confirm a similar diagnostic accuracy as the current clinical gold standard DaTScanTM, nigrosome MRI may replace DaTScanTM in the standard clinical setting.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Auer, D.
Morgan, P.
Keywords: Parkinson's disease diagnosis, Diagnostic tests, Magnetic resonance imaging, Biochemical markers
Subjects: W Medicine and related subjects (NLM Classification) > WL Nervous system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 37023
Depositing User: Schwarz, Stefan
Date Deposited: 10 Jan 2017 11:26
Last Modified: 13 Oct 2017 16:50

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